Plumbagin induces cell death through a copper-redox cycle mechanism in human cancer cells

Abstract

Plumbagin, a naphthoquinone derived from the medicinal plant Plumbago zeylanica has been shown to exert anticancer and anti-proliferative activities in cells in culture as well as animal tumor models. In our previous paper, we have reported the cytotoxic action of plumbagin in plasmid pBR322 DNA as well as human peripheral blood lymphocytes through a redox mechanism involving copper. Copper has been shown to be capable of mediating the action of several plant-derived compounds through production of reactive oxygen species (ROS). The objective of the present study was to determine whether plumbagin induces apoptosis in human cancer cells through the same mechanism which we proposed earlier. Using 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt assay, 3-(4,5-B-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay for cell growth inhibition, histone/DNA ELISA, homogeneous caspase-3/7 assay for apoptosis as well as alkaline comet assay for DNA single-strand breaks detection in this report, we confirm that plumbagin causes effective cell growth inhibition, induces apoptosis and generates single-strand breaks in cancer cells. Incubation of cancer cells with scavengers of ROS and neocuproine inhibited the cytotoxic action of plumbagin proving that generation of ROS and Cu(I) are the critical mediators in plumbagin-induced cell growth inhibition. This study is the first to investigate the copper-mediated anticancer mechanism of plumbagin in human cancer cells and these properties of plumbagin could be further explored for the development of anticancer agents with higher therapeutic indices, especially for skin cancer.

Role of Novel Nutraceuticals Garcinol, Plumbagin and Mangiferin in the Prevention and Therapy of Human Malignancies: Mechanisms of Anticancer Activity

“…As a mechanism, we found that plumbagin down-regulates Bcl-2 expression and NF-κB activity and that ectopic expression of Bcl-2 was able to attenuate plumbagin-induced effects. Plumbagin has also been shown to inhibit proliferation, and induce apoptosis in Her2/neu-overexpressing SKBR3 breast cancer cells (Nazeem et al 2009). …”

“…It also induced a change in Bax/Bcl-2 ratios and activation of caspase-9 resulting in apoptotic cell death. In A-431 cells, it has been reported that the biological action of plumbagin is mediated through a mechanism that involves redox recycling of transition metal ion copper (Nazeem et al 2009). There are some other reports on the anticancer ability of plumbagin against melanoma cells as well (Mandala Rayabandla et al 2010;Prasad et al 1996).…”

Plumbagin alters telomere dynamics, induces DNA damage and cell death in human brain tumour cells

“…The concentration of plumbagin at 2.5 M and 3.0 M both for 48 h, were used for breast cancer cells MCF-7 and MDA-MB-231 [28] and A549 lung cancer cells [29]. However, for a similar duration of treatment, prostate cancer cells and skin carcinoma cells showed IC 50 at 7.5 M and 25 M, respectively [30,31]. We observed that IC 50 values range from 2.5 to 5.5 M for a 48 h. Plumbagin treatment in brain cancer cellswhich is similar to the previously reported values.…”

“…Studies on human cancer cells have shown that plumbagininduced apoptotic cell death is mediated through generation of reactive oxygen species (ROS) [27,30,31,33]. Furthermore, induction of ROS may lead to DNA damage [27,30,34].…”

Histo-Chromatographic Finger Printing Profiles of the Root of Plumbago zeylanica Linn and Quantification of Marker Compound, Plumbagin

“…ROS molecules like superoxide, hydroxyl radical, and hydrogen peroxide cause oxidative damage to protein, DNA and phospholipids. 5,6 Thus having the properties of being a reactive oxygen species (ROS) generator and apoptosis inducing agent, plumbagin has recently been implicated with altering multiple cancer -signaling pathways and reported to have shown immense potentials in anticancer (such as breast, prostrate, ovarian, lung, liver, pancreatic, renal, cervical and skin cancer, also in myeloma and leukemia) [7][8][9][10][11][12][13][14] therapy and in radiation therapy as the chemosensitizer and radiosensitizer. [15][16][17] Genus Plumbago(Plum-Bay-go)of the family Plumbaginaceae is comprised of about 17 species.…”